Hematologic Grade Research Articles

Daratumumab maintenance after autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma

Objective: This study aimed to evaluate the efficacy and safety of daratumumab as a maintenance treatment after autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between May 1, 2022 and June 30, 2023 were retrospectively analyzed. Results: Fifteen patients (11 males and 4 females) with a median age of 58 (41-72) years were included. Thirteen patients did not receive daratumumab during induction therapy and auto-HSCT, 6 patients had renal impairment, and nine patients had high-risk cytogenetics. The median infusion of daratumumab was 12 (6-17) times, and the median duration of maintenance was 6 (1.5-12) months. The treatment efficacy was evaluated in all 15 patients, and daratumumab maintenance therapy increased the rate of stringent complete response from 40% to 60%. The renal response rate and median estimated glomerular filtration rate of six patients with RI-NDMM were also improved. During daratumumab maintenance therapy, the most common hematological grade 3 adverse event (AE) was lymphopenia [4 of 15 patients (26.67%) ], whereas the most common nonhematologic AEs were infusion-related reactions [7 of 15 patients (46.67%) ] and grade 3 pneumonia [5 of 15 patients (33.33%) ]. The five patients with pneumonia were daratumumab naive [5 of 13 patients (38.46%) ], with a median of 8 (6-10) infusions. Among them, the chest computed tomography of three patients showed interstitial infiltrates, and treatment with methylprednisolone was effective. With a median follow-up of 12 months, the 1-year overall survival rate was 93.33%, and only one patient died (which was not related to daratumumab treatment) . Conclusions: Daratumumab was safe and effective as a maintenance agent for post-auto-HSCT patients with NDMM, and AEs were controllable. The most common nonhematologic AE was grade 3 pneumonia, and a less dose-intense maintenance regimen for the first 8 weeks could reduce the incidence of pneumonia.

Abstract B034: A phase 2 basket study of the oral MDM2 inhibitor milademetan for MDM2-amplified advanced solid tumors (MANTRA-2)

Abstract Milademetan is an oral, selective, small molecular inhibitor of the MDM2-p53 complex that reactivates p53 to induce cancer cell apoptosis and tumor regressions in nonclinical models. Clinically, MDM2 gene amplification (amp) occurs in 1–2% of advanced solid tumors and is associated with a poor prognosis. Preliminary antitumor activity was seen in patients with MDM2 amp and TP53 wild-type (WT) tumors in a phase 1 clinical trial [Tirunagaru et al. AACR-NCI-EORTC 2021]. We conducted a phase 2 basket study to evaluate the efficacy of milademetan in patients with advanced or metastatic solid tumors (except liposarcoma, intimal sarcoma, and primary CNS tumors) with MDM2 copy number (CN) ≥8 and WT TP53 status based on local next-generation sequencing (NGS) (NCT05012397). Milademetan was administered at 260 mg on days 1–3 and 15–17 of a 28-day cycle. Tumor assessments were performed every 8 weeks (RECIST v1.1). MDM2 CN was retrospectively analyzed centrally using a commercial NGS assay, which also allowed correlation with other co-occurring alterations. As of June 23, 2023, 39 patients were enrolled with 13 distinct tumor types. The most common histologies were biliary tract cancers (8, 20.5%), sarcomas (7, 17.9%), and breast cancer (6, 15.3%). Median number of prior systemic therapies was 3 (range 0–12). Thirty-eight patients were evaluable for safety. The most common hematologic grade 3/4 adverse events (AEs) related to milademetan were thrombocytopenia (26.3%), neutropenia (15.8%), and anemia (10.5%). All grade treatment-related AEs (>15% incidence) included thrombocytopenia (44.7%), nausea (42.1%), fatigue (36.8%), vomiting (31.6%), anemia (23.7%), diarrhea (23.7%) and neutropenia (18.4%). No bleeding or neutropenic sepsis events were reported, and no grade 5 events were observed. The dose reduction rate was 13.2%, and 7.9% of patients discontinued milademetan due to AEs. Central tumor testing was available on 30 (76.9%) patients and only 2 (6.7%) patients demonstrated MDM2 CN below the threshold of 8. Thirty-two patients were efficacy evaluable and had confirmed CN ≥8 or pending central analysis. Five partial responses (15.6%) were observed (4 unconfirmed, 1 confirmed) with one each in lung adenocarcinoma (co-alteration of EGFR + KRAS), pancreatic (KRAS), bladder (pending), gastric cancer (DNAB1-PRKACA) and endometrial sarcoma (CCND2). No clear correlation between MDM2 CN and tumor regression was observed. The median progression-free survival was 3.3 months (95% CI, 2.5–6.1). The longest patient on milademetan therapy was 41 weeks (biliary, best RECIST 1.1 response SD with –29% tumor reduction). Ten patients are currently ongoing. Milademetan monotherapy demonstrated clinically meaningful antitumor responses with a manageable toxicity profile in a variety of MDM2 amp, TP53 WT solid tumors, including those with other oncogenic drivers such as KRAS. Rational combination strategies with milademetan should be considered in tumors with WT TP53 to further enhance durable anti-tumor activity. Citation Format: Ecaterina E. Dumbrava, Christopher T. Chen, Gregory M. Cote, Glenn J. Hanna, Thomas E. Stinchcombe, Bradley Sumrall, Trisha Wise-Draper, Mohammed Kanaan, Steven Duffy, Christopher Sumey, Patrick Cobb, Naisargee Shah, Bo Zhang, Nora Ku, Robert C. Doebele, Mrinal Gounder. A phase 2 basket study of the oral MDM2 inhibitor milademetan for MDM2-amplified advanced solid tumors (MANTRA-2) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B034.

Phase I study of bendamustine, rituximab, ibrutinib, and venetoclax in relapsed, refractory mantle cell lymphoma

This dose-finding study evaluated safety of venetoclax plus Bendamustine-Rituximab-Ibrutinib in relapsed/refractory MCL. Six 28-day cycles were administered in a 3 + 3 dose-escalation design. Dose level 1 (DL1) included Bendamustine 90 mg/m2 on day 1-2, Rituximab 375 mg/m2 on day 1, and Ibrutinib 560 mg daily. Venetoclax was dosed with ramp-up and at 400 mg starting in Cycle 2 for 5 days. The most common adverse events were thrombocytopenia (80%), constipation (60%), and fatigue (60%). Rare hematologic grade 3-4 AEs, 1 dose-limiting toxicity at DL1 (prolonged grade 3 thrombocytopenia), and delayed hematologic toxicity were observed. DL-1 with Bendamustine dose-reduced to 70 mg/m2 (n = 3) revealed no significant toxicity. The overall and complete response rates were both 80% (8/10). This study underscored that venetoclax combined with chemoimmunotherapy is complicated by hematologic toxicity, limiting future development. Although a maximum tolerated dose was not formally established given early study closure, this study demonstrated preliminary tolerability and efficacy of Bendamustine-Rituximab-Ibrutinib-Venetoclax at DL-1.

Daratumumab Maintenance after Autologous Hematopoietic Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma

Background: Maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT) is a standard of care in newly diagnosed multiple myeloma (NDMM). Lenalidomide maintenance after transplantation is the most frequently recommended regimen. Daratumumab has been increasingly used as a maintenance drug in NDMM. However, there is no enough clinical information about daratumumab as maintenance strategy after ASCT. This study is aim to evaluate the efficacy and safety of daratumumab as maintenance after ASCT for NDMM. Patients and Methods: Clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between 1 May 2022 and 30 June 2023 were retrospectively analyzed. Daratumumab-naive patients received weekly dosing (16mg/kg) for the first 8 weeks. Results: Fifteen patients (11 males and 4 females) with median age of 58 years (41～72 years) , were included. Thirteen patients were daratumumab native, 6 patients had renal impairment, and 2 patients with high-risk cytogenetics. The median infusion times of daratumumab were 12 (6～17) times. Efficacy was evaluable in all 15 patients，and daratumumab maintenance therapy increase the rate of stringent complete response (from 6 [40%] to 9 [60%] ) by 20%，improved the renal response rate and median eGFR in patients with renal injury. During maintenance therapy with daratumumab, the most common hematological grade 3 adverse events(AE) were lymphopenia (4 [26.67%] of 15 patients), non-hematologic adverse events were infusion-related reactions (7 [46.67%] of 15 patients) and grade 3 pneumonia (5 [33.33%] of 15 patients). These 5 pneumonia patients were daratumumab naive ( 5 [38.46%] of 13 patients) , with median 8 (6～10)infusions. Among them, 3 patients chest CT showed interstitial infiltrates, and combination of methylprednisolone was effective. With a median follow-up of 12 months, one patient had died (not related to daratumumab treatment), 1-year OS rate was 93.33%. Conclusions: Daratumumab was safe and effective as a maintenance agent for post-ASCT patients with NDMM, and adverse events were controllable. The most common AE is grade 3 pneumonia, maybe a less dose-intense maintenance regimen for the first 8 weeks can reduce the incidence of pneumonia.

Results of an Open-Label Phase 1 Study Repurposing Oral Metformin and Nelfinavir in Combination with Subcutaneous Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Background: GLUT4 inhibition via the use of a protease inhibitor, such as nelfinavir (NEL), is an attractive therapeutic option in multiple myeloma (MM), given the dependence of MM cells on glucose. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor, such as metformin (MET), may counter the possibility of therapeutic resistance to GLUT4 inhibition in MM cells, showing synergistic promise (Dalva-Aydemir et al., Clin Can Res 2015). In addition to GLUT4 inhibition, NEL also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (BOR) (Driessen et al., Blood 2018). Thus, this study evaluated the safety and tolerability of repurposing MET and NEL, in combination with BOR for the treatment of relapsed/refractory MM (RRMM) that had progressed on all standard of care (SOC) therapies. Methods: This trial utilized a 3+3 dose escalation design with 3 dose levels planned for up to a maximum of six (21-day) cycles. MET was administered for 14/21 days and started at a dose of 500 mg BID with plans to be investigated at a maximum dose of 1000 mg BID. NEL was administered for 14/21 days and started at a dose of 1250 mg BID with plans to be investigated to a maximum dose of 2500 mg BID. SubQ BOR was administered on days 1, 8, and 15 of a 21-day cycle at a dose of 1.3 mg/m 2 to a portion of patients. Patients with RRMM were required to have had 2 prior lines of therapy and prior exposure to proteasome inhibitors (PIs), immunomodulators (IMiDs), and Anti-CD38 monoclonal antibodies. The primary objective was to determine the maximal tolerated dose (MTD) of this combination. The secondary objective was to evaluate the safety as well as the overall response rate (ORR) of this combination. This trial was funded by the Helen Diller Family Foundation. Results: From 4/2019 until 9/2022, nine patients were accrued with a median age of 65 (range: 42-81) that received a median of 7 prior lines of therapy (Range: 6-13). All but one patient had a prior autologous stem cell transplant. Only one patient was not triple-class refractory, and 2/3 rd (n = 6) also had prior anti-BCMA therapy. The first three patients received only MET (500 mg BID) and NEL (1250 mg BID) at the first dose level for up to one cycle before experiencing progressive disease and coming off the study. Given the limited activity of MET and NEL in the initial treatment of these three patients, two subsequent amendments to the protocol allowed for the upfront addition of BOR 1.3 mg/m2 to the original combination, as well as shortened the DLT evaluation period from two cycles to just one. Thus, the following six patients received MET (500 mg BID) and NEL (1250 mg BID) at the first dose level in addition to weekly BOR at 1.3 mg/m2. Four (44%) patients experienced grade 3+ hematological AEs and six (67%) experienced grade 3+ non-hematological AEs. The most common hematologic grade 3+ AE observed was anemia (44%). The nonhematologic grade 3+ AEs observed were dyspnea, fatigue, nausea, and vomiting (11% each). None of the AEs were possibly related to treatment, suggesting good overall safety of the combination. While eight of nine patients have since died of progressive disease, no deaths were attributable to the treatment. All six patients who received BOR upfront with MET and NEL were previously refractory to BOR in prior lines of therapy; however, none had received BOR as their last line of therapy prior to accrual to this study. Four of these six patients had progressive disease after one cycle of therapy and went off study. However, the remaining two were able to receive 2 or more cycles of therapy, with one experiencing an unconfirmed minor response (MR) in the first cycle and the other experiencing stable disease (SD) for all six cycles. The patient who experienced SD was safely able to transition to a subsequent clinical trial utilizing an anti-BCMA bispecific antibody therapy and remains alive at the time of this analysis. The study was closed before accrual to the next dose level was started. Conclusions: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of RRMM. While no ORR was observed, identification of biomarkers used for selection of patients with no other SOC options who could experience at least SD responses may be beneficial in allowing this combination to slow or stabilize the disease progression until other novel therapies or clinical trials are available.

Preliminary Outcome and Quality of Life among Geriatric Head and Neck Cancer (GHNC) Patients Treated with Institutional Nimorad (Nimotuzumab-Modulated Radiotherapy) Protocol

<h3>Purpose/Objective(s)</h3> Treatment for geriatric head and neck squamous carcinomas (GHNC) remain challenging due to multiple patient and treatment related factors. We analyzed radical intent treatment for GHNC with modulated arc therapy (VMAT) and concurrent Nimotuzumab (Nim) as part of prospectively maintained database NIMORAD (Nimotuzumab-modulated radiotherapy) for early clinical outcome and toxicity. <h3>Materials/Methods</h3> 30 (M:25, F:5) patients of biopsy proven locally advanced squamous cell carcinomas staged by whole body PETCT scan (stage III-IVB) were analyzed. All were above 70 years (Range: 70-88 years) and received uniform treatment with VMAT (66-70 Gy/33 fractions) and Inj Nim 200mg weekly for 6 cycles. Cisplatin ineligibility was in terms of age>70, multiple comorbidities, deranged kidney or hearing functions. Patients more than 80 years were selected for NIMORAD only if baseline G8 screening score was 14 or more. All the cases were discussed in Institutional GHNCC (Geriatric head neck cancer clinic). Institutional comprehensive geriatric assessment was followed with G8 scoring, activities of daily living (ADL) by Katz index, nutritional scoring by subjective global assessment (SGA) and co-morbidity scoring with Charlsons comorbidity index (CCI). Primary analysis was related to survival (disease free survival, local control and overall survival) and toxicity. First surveillance PETCT was between 10-14 weeks post treatment. The toxicities were graded as per CTCAE version 3.0. Follow up was every 3 months with 2^nd surveillance PETCT 6-8 months depending on 1^st response. Statistical analyses were carried out using statistical software. <h3>Results</h3> Median follow-up, age and G8 screening score were 18 months, 77 years and 13 respectively. 83.3% patients were male and 60% had oropharyngeal primaries with 10% HPV positive. At 1^st follow up complete response (CR) at primary site was 85% on both FOL and PETCT. Till last follow up 60% had complete response, 16% had loco-regional failure and 2% distant metastases. Nine patients died till last follow up and 5 were lost to follow up. All P16 positive patients (3) had loco-regional and distant control till last follow up. The acute grade 2 mucositis and dysphagia were 70% and 90% respectively with 30% grade 3 dysphagia. Long term tube dependency rates were 10% mostly beyond 80 years. 20% had hematological grade 2 plus toxicity and 10% had skin rash due to Nim. The other notable adverse events were grade 3 trismus, osteoradionecrosis and aspiration pneumonia between 2-5%. Median Katz index was 5, SGA and CCI were higher for hospitalized patients. <h3>Conclusion</h3> This single Institution NIMORAD protocol for GHNC shows promising clinical results with no additional toxicity profile. This can be an option for improved disease control in locally advanced GHNC. Future large cohort prospective documentation with longer follow up is warranted.

Apatinib plus vinorelbine versus vinorelbine for metastatic triple-negative breast cancer who failed first/second-line treatment: the NAN trial

While therapies such as chemotherapy combined with immunotherapy, sacituzumab govitecan, and PARP inhibitors are available for metastatic TNBC, on disease progression after these therapies, the mainstay of therapy is chemotherapy. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with advanced TNBC with failed first/second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine or vinorelbine with apatinib in 28-day cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.9 months vs. 2.0 months; hazard ratio, 1.82; 95% confidence interval [CI], 1.06 to 3.11; P = 0.026). Median OS was 11.5 months with apatinib plus vinorelbine and 9.9 months with vinorelbine (HR,1.01; 95% CI, 0.51 to 1.97; P = 0.985). The ORR was 9.1% in the apatinib plus vinorelbine group and 6.3% in the vinorelbine group (P = 0.667). The most common treatment-related hematologic grade 3–4 adverse events in apatinib plus vinorelbine group, were leukopenia, granulocytopenia, anemia, and thrombocytopenia. no treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Collectively, adding apatinib to vinorelbine shows a promising benefit in PFS compared to vinorelbine monotherapy, with an excellent toxicity profile, warranting further exploration.

P515: LOWER-INTENSITY CPX-351 + VENETOCLAX FOR PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA WHO ARE UNFIT FOR INTENSIVE CHEMOTHERAPY

Background: CPX-351 (Europe: Vyxeos® liposomal; United States: Vyxeos®) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults in Europe and patients aged ≥1 year in the United States who are candidates for intensive chemotherapy (IC). However, the appropriate dosage of CPX-351 in patients unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit patients with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Aims: Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Patients who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Patients are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 patients enrolled by 15 September 2021, with a data cutoff of 2 December 2021: 4 patients in the DEP at dose level 1 (CPX-351 20 units/m2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 patients in the DEP at dose level 2 (CPX-351 40 units/m2 + VEN 400 mg), and a total of 20 patients in the DEP and EP at dose level 1b (CPX-351 30 units/m2 + VEN 400 mg), which was established as the recommended phase 2 dose. Patients were considered unfit for IC based on age ≥75 years (n=15) or health (Eastern Cooperative Oncology Group performance status of 2 to 3 and/or comorbidities [n=16]). Median age was 74 years (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of patients were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) patients; no nonhematologic grade ≥3 TEAE was reported in >10% of patients. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n=1), worsening lung infection (n=1), and disease progression (n=2). Median (interquartile range) recovery times were 30 days (22, 34.5) to neutrophils ≥500/μL and 21 days (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) patients with an evaluable remission assessment. All 16 of these patients achieved remission (CR or CRi) after the first treatment cycle. MRD negativity was achieved by 12/16 (75%) patients with CR or CRi, primarily after Cycle 1 (Cycle 1: n=8; Cycle 2: n=2; Cycle 3: n=1; Cycle 4: n=1). Survival data are not yet mature. Summary/Conclusion: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of patients.

Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML

AbstractPANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.

Lower-intensity CPX-351 + venetoclax for patients with newly diagnosed AML who are unfit for intensive chemotherapy.

7031 Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients (pts) who are candidates for intensive chemotherapy (IC) and aged ≥1 year in the US and adults in Europe. However, the appropriate dosage of CPX-351 in pts unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit pts with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Pts who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Pts are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 pts enrolled by 9/15/2021, with a data cutoff of 12/2/2021: 4 pts in DEP at dose level 1 (CPX-351 20 units/m2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 pts in DEP at dose level 2 (CPX-351 40 units/m2 + VEN 400 mg), and a total of 20 pts in DEP and EP at dose level 1b (CPX-351 30 units/m2 + VEN 400 mg; established as the recommended phase 2 dose). Pts were unfit for IC based on age ≥75 y (n = 15) or health (ECOG PS of 2 to 3 and/or comorbidities [n = 16]). Median age was 74 y (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of pts were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) pts; no nonhematologic grade ≥3 TEAE was reported in &gt; 10% of pts. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n = 1), worsening lung infection (n = 1), and disease progression (n = 2). Median (IQR) recovery times were 30 d (22, 34.5) to neutrophils ≥500/μL and 21 d (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) evaluable pts. All 16 of these pts achieved remission (CR or CRi) after the first cycle. MRD negativity was achieved by 12/16 (75%) pts with CR or CRi, primarily after Cycle 1 (Cycle 1: n = 8; Cycle 2: n = 2; Cycle 3: n = 1; Cycle 4: n = 1). Survival data are not yet mature. Conclusions: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of pts. Clinical trial information: NCT04038437.

Phase I study of epacadostat in combination with sirolimus in advanced malignancy.

2575 Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients with advanced solid tumors, with plans for an expansion phase II study in patients with advanced recurrent lung cancer once maximum tolerated dose (MTD) was defined. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at day -7 followed by 1mg/d with E added on day 1 of Cycle 1 starting at 300mg bid in a 28d cycle at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400 bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. Enrollment continued until Dose limiting toxicity (DLT) which was defined as grade 3 hematologic toxicities or grade 3 or 4 non-hematologic toxicities up to Cycle 2 day 1. MTD was defined as DLT not exceeding 33% of subjects. Results: The phase I study enrolled 15 patients, with 9 patients evaluable. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). DLT was not observed up to level 3. Adverse events attributed to SE were Grade 1 Diarrhea (2), stomach pain (1); elevated liver enzymes (ELE) (1), decreased white blood cell (1), anorexia (1), hypokalemia (1), dizziness (1), skin rash (1); Grade 2 ELE (1), Anemia (1), Vertigo (1), Constipation (1), Nausea (2); Grade 3: Diarrhea (1), serotonin syndrome (1), dyspnea (1). The best response observed was stable disease in 3 patients, 5 patients had disease progression and 1 patient was not assessable for response due treatment discontinuation related to side effect of serotonin syndrome. The Expansion Cohort (Part 2) did not proceed since the sponsor decided to discontinue further development of E. Conclusions: The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities. There were few grades 3 toxicities. SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients with lung cancer resistant to checkpoint inhibitor is worth additional exploration. Clinical trial information: NCT03217669.

Induction chemotherapy using carboplatin and paclitaxel followed by hypofractionated radiation therapy in locally advanced hypopharyngeal and laryngeal squamous cell cancer.

e18039 Background: Head and neck cancer (HNC) is one of the most common cancers in Pakistan due to excessive use of chewable tobacco. Locoregional control is not optimum due to advanced stage at presentation and suboptimal cancer treatment facilities. Innovations in treatment schedules are of utmost importance to tackle the problem of overburden of patients and shortage of resources for radiation therapy in the country. The aim of the study is to assess the efficacy of induction chemotherapy with carboplatin and paclitaxel (CP) followed by hypofractionated radiotherapy (HRT) in patients with locally advanced laryngeal and hypopharyngeal cancers. Methods: A total of 68 patients with biopsy proven HNC were included. Patients having primary tumor in larynx (35) and hypopharynx (33) with TNM stage III to IVB were selected. The patients were planned for three cycles of CP every three weeks in a dose of AUC = 5 and 175 mg/m² on day 1 of each cycle respectively. After three cycles of chemotherapy, patients were planned for hypofractionated radiotherapy (HRT). A total of 55 Gray (Gy) was planned with 2.75 Gy per fraction and five fractions a week. Spinal cord dose was limited to 33 Gy. Response Evaluation Criteria in Solid Tumor (RECIST) was used to assess various response rates using computed tomography (CT) six weeks after completion of HRT. Patients were followed for a median of 27.4 months to assess disease free survival (DFS) and overall survival (OS). Results: 61 patients (90%) were available for assessment. Others were excluded due to inability to complete the planned treatment. Eight patients (12%) showed disease progression during treatment and were switched to other form of treatment. Seven patients (10%) showed grade 3 mucosal toxicity and needed treatment interruption. Thirteen patients (19%) showed hematological related grade 1-2 toxicity. The complete response (CR) was seen in 18 (35%), partial response (PR) in 27 (52%) and stable disease SD in 7 (13%) patients. Three year DFS and OS were 45% and 58% respectively. Mean and median DFS (year) were 3.67±0.13 (95% confidence interval [CI] 3.19-3.94) and 4.24±0.43 (CI 3.46-4.52) respectively. Mean and median OS (year) were 3.89±0.11 (CI 3.72-4.15) and 4.12±0.23 (CI 3.87-4.38) respectively. Conclusions: Induction CP followed by HRT is a reasonable in locally advanced laryngeal and hypopharyngeal cancer. A larger phase III randomized trial will be better to define its role before routinely recommending this schedule in these patients.

Midostaurin in advanced systemic mastocytosis: A systematic review and meta-analysis.

e19084 Background: Midostaurin, an oral multikinase inhibitor including inhibition of KIT D816V, is approved for the treatment of advanced systemic mastocytosis (SM). Few studies have investigated the use of midostaurin in patients with advanced SM, but the data on its efficacy and safety in this population remains limited and uncertain. Therefore, we conducted this systematic review and meta-analysis to better assess the efficacy and safety of midostaurin in advanced SM. Methods: We systematically searched the following databases: PubMed/MEDLINE, Embase, and Cochrane through February 02, 2022, to include all studies that assessed the effect of midostaurin on clinical outcomes of patients with advanced SM. Our primary outcome was the overall response rate (ORR). The secondary outcomes included the rates of progressive disease (PD), stable disease (SD), and treatment discontinuation due to adverse events (AEs). All statistical analyses were performed using Open Meta Analyst (CEBM, University of Oxford). Pooled rates and corresponding 95% confidence intervals (CI) were calculated using DerSimonian-Laird/Random-effects approach. Results: Four studies (two clinical trials and two observational studies) with a total of 156 patients with advanced SM were included in the pooled analysis. The mean age of the patients was 59.6±15.8 years, and males represented 64.7% of total patients. The most common subtype of advanced SM was SM associated with hematological neoplasm (59%) followed by aggressive SM (23.1%). Three studies reported the KIT D816V mutation status, and 85.2% of patients were positive for KIT D816V mutation. The mean duration of treatment with midostaurin was 10±15.3 months. The pooled ORR was 60% (95% CI 46.5%-73.5%) over a mean follow-up duration of 41.1±38.7 months. The PD and SD rates were 12.8% (95% CI 7.6%-18%) and 10.6% (5.3%-15.9%), respectively. Treatment discontinuation due to AEs occurred in 25.6% (95% CI 18.8%-32.4%). The most common hematological grade ≥3 treatment-related AE was anemia (29%), while fatigue (7.1%) was the most common non-hematological grade ≥3 treatment-related AE. Conclusions: Our study demonstrated that midostaurin is very effective in patients with advanced SM with an acceptable safety profile. Our meta-analysis is hampered by a limited number of studies, a small sample size, and a lack of a control group. Future large-scale comparative studies are warranted to evaluate the efficacy and safety of midostaurin in these patients.

Modified docetaxel, cisplatin, and 5-fluorouracil combination regimen and capecitabine maintenance in metastatic gastric cancer: toxicity and efficacy results.

Little progress has been made, and there is an unmet medical need for treatment of metastatic gastric cancer (MGC). Docetaxel + cisplatin + 5-fluororacil (DCF) combination is an effective regimen with high rate of toxicity and is not well tolerated. We aimed to evaluate the efficacy and toxicity of a modified DCF (mDCF) combination regimen and capecitabine maintenance in MGC. Data of MGC patients were treated with first-line mDCF regimen (two weekly docetaxel 60mg/m2 day 1 iv, cisplatin 50mg/m2 day 1 iv, 5-fluouracil 400mg/m2 day 1 iv push, 2400mg/m2; day 1-day 2 iv infusion, leucovorin 400mg/m2 day 1 iv push) were recorded. Capecitabine maintenance was given as 2500mg/m2/ day 1-day 14 po, every 3weeks, to patients who do not have progressive disease and grade 3 treatment-related toxicity. A retrospective analysis was made. Forty patients were included. Mean age was 53 ± 11. Thirty-two patients had de novo metastasis. All patients' performance status was ECOG 1 or 2 (32/8). Median number of mDCF cycles given was 9 (min-max: 1-23). Overall response rate was 47.5%. Ten patients (25%) received capecitabine maintenance. Grade 3/4 toxicity was seen in 20 patients (50%). Hematologic grade 3/4 toxicity occurred in 13 patients (32.5%), and grade 3/4 neutropenia occurred in 11 patients (27.5%) and in 15 cycles. Nonhematologic grade 3/4 toxicity was seen in 7 patients (17.5%). Median follow-up time was 17.2months. Median time to progression (TTP) was 10.8 ± 1.9months (95% CI: 6.89-14.64). Median overall survival was 14.7 ± 1.73months (95% CI: 11.30-18.10). mDCF protocol was a tolerable chemotherapy regimen for the first-line treatment of MGC with higher ORR and longer TTP compared to standard DCF protocol. Capecitabine maintenance might increase TTP.

Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study

BackgroundAge and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. MethodsWomen with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants. ResultsOne-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16–1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26–0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59–0.90). ConclusionsNon-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups.

Prospective feasibility study of neoadjuvant dose-dense paclitaxel plus carboplatin with bevacizumab therapy followed by interval debulking surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer patients.

This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3weeks consisting of paclitaxel (80mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0mg/mL × min.) on day 1; and bevacizumab (15mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. Twenty-four patients were included in this study. The median age was 55.5years (37-80years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

OAB-013: Iberdomide (IBER) in combination with dexamethasone (DEX) and daratumumab (DARA), bortezomib (BORT), or carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM)

OAB-013: Iberdomide (IBER) in combination with dexamethasone (DEX) and daratumumab (DARA), bortezomib (BORT), or carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM)

P-160: Efficacy and safety of induction therapy with IAd versus IRd regimen in fragile elderly patients with newly diagnosed multiple myeloma: results of a prospective multicenter clinical trail

<h3>Background</h3> Fragile elderly patients with multiple myeloma (MM) have low survival rate due to complications, poor tolerance and complianceand lack of effective treatment. This prospective multicenter non-randomized controlled study designed to assessment the efficacy and safety of IAd versus IRd in fragile elderly NDMM. <h3>Methods</h3> This ongoing trial is conducted at 14 hospitals. Inclusion criteria was aged ≥ 65 years, IMWG GA score ≥ 2 or Mayo geriatric vulnerability scoring system defined as vulnerable. Patients with acute cardiovascular and cerebrovascular events were excluded. Schemes included IAd (ixazomib 4mg d1,8,15, liposome doxorubicin 40mg d1,dex 20mg d1,8,15,22), IRd (ixazomib 4mg d1,8,15, lenalidomide 25mg d1-14, dex 20mg d1,8,15,22), in 4-week cycles. For patients with effective response (≥ PR) after 6 to 8 cycles, Id maintenance initiated until progression. The study was powered for a primary endpoint of ORR,with PFS,OS,toxicity,health-related Qol as secondary endpoints. This study planned to enroll 120 patients, 60 in each group (chiCTR1900024917). <h3>Results</h3> From Oct 2019 to May 2021, 95 patients were enrolled, median age 71(65-88) yrs, 29.5% of patients ≥75 yrs,18.9% of patients with renal insufficiency(eGFR < 30ml/min, n=13).Efficacy was evaluated in 89 patients,6 were not evaluated, of them,1 had not completed first cycle,2 had dropped out after first cycle,and 3 died in the first course. All patients with renal insufficiency (except for one case), paraplegia, or bedridden were enrolled in IAd group. At a median follow-up of 10 mons (1-20), total ORR was 80.9%, with 80.9% (38/47) in IAd and 81.0% (34/42) in IRd. Median PFS was 16 mons in IAd and was not achieved in IRd. Median OS was not achieved in both two groups,with 12 mon-OS at 81.0%. Cytogenetic high-risk was defined by t(4;14),t(14;16),t(14;20),del(17p) or 1q21 amplification.64.2% of patients stratified as high-risk, 21.0% of patients had ≥ 2 high-risk cytogenetic, median OS was 14 mons, while the median OS of patients with 1 or none high-risk genetic was not achieved (p=0.05).9.5% patients developed hematological grade 3 or above,13.7% patients developed gastrointestinal AE above grade 3 (IAd, n=10; IRd, n=3),13.7% patients with pneumonia(IAd, n=9; IRd,n=4). IRd regimen saw more serious neurotoxicity,5 patients had delirium, mental disorder or cerebral infarction. Fragile elderly patients are relatively vulnerable to death.16 patients died, included 7 deaths due to progression, 4 early deaths (≤60 days),4 treatment abandonment, and 1 unexplained sudden death. <h3>Conclusion</h3> Overall efficacy and safety results support the use of IAD or IRD as frontline therapy for fragile elderly MM patients. Both regimenswere effective, with an overall response rate of 80.9% and 12-month OS of 81.0%. AE were tolerable. Mortality rate are comparably high in fragile elderly MM patients,it is still a challenge for treatment.

582Cost-effectiveness of AC-TH compared with TCH in new adjuvant therapy of breast cancer

Abstract Background To analyze the cost-effectiveness of Doxorubicin/cyclophosphamide/Paclitaxel/trastuzumab (AC-TH) and Docetaxel/Carboplatin/trastuzumab (TCH). Methods A Markov model was built to simulate the process of breast cancer events and death occurred in both AC-TH and TCH armed patients and to choose a suitable chemotherapy method. Data were collected from the clinical trials, some publicized literatures and patients’ diaries of a large Chinese comprehensive hospital. The cost-effectiveness analysis of two regimens and sensitivity analysis were performed using a Markov model. Results We identified 41 breast cancer patients at Hangzhou First People’s Hospital, among whom 15 (60%) had a partial response for AC-TH treatment and 13 (81.25%) had a partial response for TCH treatment. No cardiac toxicity was observed. Hematologic grade 3 or 4 toxicities were observed in 1 of 28 patients. Nonhematologic grade 3 or 4 toxicities with a reverse pattern were observed in 6 of 29 patients. The mean QALY gain per patient compared with TCH was 0.25 with ACTH, while the incremental costs were $US 13,142. The incremental cost-effectiveness ratio (ICER) of AC-TH versus TCH was $US 52,565 per QALY gained. Conclusions TCH neoadjuvant chemotherapy was feasible and active in HER2-overexpressing breast cancer patients in terms of the pathological complete response, complete response, and partial response rates and manageable toxicities. Key messages breast cancer; neoadjuvant chemotherapy; pharmaceutical economics; Markov model; cost-effectiveness analysis.

Abstract 1620: Efficacy and safety of ICIs in lung cancer patients with interstitial pneumonia

Abstract Background: ICIs has demonstrated efficacy against metastatic lung cancer. However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with interstitial pneumonia (IP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of ICIs may outweigh the risks of pneumonitis in patients with lung cancer who have IP. We performed a pilot trial to evaluate the safety of ICIs in lung cancer patients with IP. Methods: Previously treated, inoperable NSCLC patients with IP were enrolled. Patients received anti-PD-1/L1 as monotherapy or in combination with other agents, respectively. Results: A total of 21 lung cancer patients were selected, including 15 (71.4%) male and 6 (28.6%) female with a median age of 62. None experienced drug related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of ICIs treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 11 had experienced a partial response. Conclusion: ICIs therapy may be feasible in lung cancer patients with IP. Citation Format: Yan Fu, Fuyu Gong. Efficacy and safety of ICIs in lung cancer patients with interstitial pneumonia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1620.